Photodynamic therapy is a procedure that uses photoselective (light-activated) drugs to target and destroy diseased cells. Photoselective drugs transform light energy into chemical energy in a manner similar to the action of chlorophyll in green plants. The photoselective drugs are inactive until switched on by light of a specific wavelength. This gives physicians the potential to target specific groups of cells and control the timing and selectivity of treatment. The result of this process is that diseased cells are destroyed with minimal damage to surrounding normal tissues.
Photodynamic therapy begins with the administration, to a patient, of a photoselective compound that is selectively taken up and/or retained by the biologic target, i.e., tissue or cells. After the photoselective compound is taken up by the target, a light of the appropriate wavelength to be absorbed by the photoselective compound is delivered to the targeted area. This activating light excites the photoselective compound to a higher energy state. The extra energy of the excited photoselective compound can then be used to generate a biological response in the target area. As a result of the irradiation, the photoselective compound exhibits cytotoxic activity, i.e., it destroys cells. By localizing the irradiated area, it is possible to contain the cytotoxicity to a specific target area. For a more detailed description of photodynamic therapy, see U.S. Pat. Nos. 5,563,262, 5,693,632, 5,354,858, 4,877,872, and 4,988,808, the disclosures of which are incorporated herein by reference.
Phorbines, pheophorbides, and derivatives of chlorophylls are a known class of photoselective compounds useful for photodynamic therapy. See, for example, U.S. Pat. Nos. 4,675,338, 4,656,186, 5,198,460, and 5,506,255. A particularly useful compound that acts as a template for further chemical modifications is the chlorin derivative known as methyl pyropheophorbide. This compound is generally produced by the following reaction scheme: ##STR1## See, U.S. Pat. No. 5,198,460.
The present inventors have found, however, that the demethoxycarbonylation step (depending on the scale of the reaction) is inconsistent in yield and in time to reaction completion. In general, the longer the reaction time, the more decomposition products are produced, which detrimentally impacts the purity and yield of the desired product. It has been found by the present inventors that, in commercial scale production, commercially available 2,4,6-collidine (2,4,6-trimethylpyridine) alone is inadequate in effecting the demethoxycarbonylation reaction, causing major decomposition of the starting pheophorbide due to much longer reflux reaction times.
Accordingly, there is a need for a method for the demethoxycarbonylation of pheophorbides that provides a consistent yield of the desired pyropheophorbide compound.
There is also a need for a method for the demethoxycarbonylation of pheophorbides that provides a reduced reaction time to completion.
There is a further need for a method for the demethoxycarbonylation of pheophorbides that provides the desired pyropheophorbide compound in improved purity.
There is a further need for a method for the demethoxycarbonylation of porphyrins on a large scale that improves the yield, lowers the reaction time, and improves the purity of the desired porphyrin compounds.